Cyclic structures are found in many important bioactive molecules, particularly alkaloids such as the tropane alkaloids, which include cocaine and its derivatives, other alkaloids such as opiates, and several classes of antibiotics. They also show great potential in other areas such as conformationally-restricted cyclic amino acids and peptides, and monosaccharides and oligosaccharides, including such molecules which are substituted with amino or other groups, and squalestatin analogues.
It is evident, therefore, that these cyclic structures, such as bicyclic and polycyclic structures, are of great importance from a medicinal point of view. Although there are many reports on the synthesis of selected examples of bicyclic and polycyclic molecules, none of these offers a general solution to the problem of synthesis of all these structural classes. There is, therefore, a great need in the art for a new general process to enable the synthesis of these compounds.
We have now developed a general approach for the synthesis of highly functionalised cyclic molecules, which involves the use of a sequence of nucleophilic addition followed by one or more ring closures (“NARC”) to construct a wide variety of enantiomerically pure cyclic compounds. These include mono-, bi- and polycyclic carbocycles, oxacycles, azacycles and thiacycles of varying, but well-defined, size, substitution pattern and stereochemistry. These compounds can be used directly or as intermediates for further syntheses, or can then be further functionalised to provide large libraries of molecules with a wide range of potential applications, for example in drug screening.